Project Summary: The lung is a major portal of entry for many devastating human pathogens including respiratory viruses, such as the SARS corona virus and avian influenza viruses. Therefore, it is critical to develop vaccines that specifically induce long-lasting protective immunity in the respiratory tract. However, a significant hurdle in the development of pulmonary vaccines is our poor understanding of cell-mediated immunity in the lung. We don't know which subpopulations of memory T cells are critical for viral clearance, how these subpopulations are established and subsequently maintained, or how these cells can be effectively generated by vaccination strategies. In the current proposal, we seek to fill these gaps in knowledge by dissecting memory T cell responses to influenza virus infection in mice. Previous studies and preliminary data demonstrate that the recall T cell response to influenza virus occurs in three distinct phases. Memory T cells already present in the airways are the first to contact antigen and mediate early control of viral replication. This is followed by the early recruitment of non-proliferating memory T cells into the lung airways from the circulation. Finally, memory cells that proliferate in response to antigen in the secondary lymphoid organs are recruited into the lung airways as effector cells. Thus, the recall response involves multiple subsets of antigen-specific memory T cells that engage the pathogen in a temporal fashion. The objective of this proposal is to determine how these memory T cell subpopulations contribute to recall responses in the lung and the capacity of different vaccine strategies to elicit these different subpopulations. We will achieve this objective by pursuing the following specific aims. First, we will identify the memory T cells that are rapidly recruited into the airways during a secondary virus challenge. Second, we will identify the mechanisms that regulate the recruitment and accumulation of memory T cells in the lung airways during the early stages of the recall response. And third, we will determine which subpopulations of memory cells are elicited by different vaccine strategies and how they contribute to recall responses. Together, these studies will extend our understanding of cellular immune responses in the lung. The data will be important for the development of vaccines that promote effective pulmonary immunity to respiratory pathogens. Relevance: Respiratory infections are a major health problem in the United States. As such, the respiratory system represents a critical target for the generation of vaccines designed to promote protective immunity against pulmonary pathogens, such as SARS virus and avian influenza. The studies proposed in this application will further our understanding of pulmonary immunity and provide important insights for the development of vaccines designed to promote long-lived cellular and humoral immunity against a variety of different pulmonary pathogens.